Composition based on diosgenin ester for topical use

ABSTRACT

The invention concerns compositions useful in therapeutics and in cosmetology. The composition comprises a diosgenin ester with linear or branched alkylated ester chain containing 1 to 30 carbon atoms selected preferably among diosgenin lactate and glycalate. The invention is applicable in dermatology by acting on the superficial musculo-aponevrotic system or on estrogen and progestenone cell receptors.

The present invention relates to a composition which is useful in humanor animal therapeutics and cosmetology, and more particularly to acomposition with local action which can be applied topically and whichcomprises a diosgenin ester.

Diosgenin, a structural analog of cholesterol, is essentially used intherapeutics because of its anti-inflammatory properties and its actionin compensating for the deleterious effects of estrogens, moreparticularly in the perimenopausal and menopausal period. It is alsoused in cosmetics and in dermatology for its antiseptic properties onthe skin.

Diosgenin can be extracted from plants of the Dioscorea genus, inparticular Dioscorea opposita, which is a plant used in traditionalChinese medicine. The extraction can be carried out by the usualtechniques, for example by ethanolic extraction, from any part of theplant, and preferably the rhizome, which has been pre-dried and ground.A method for growing plants of the Dioscorea family, in particularDioscorea floriburida and Dioscorea composita, which makes it possibleto improve the diosgenin content is described in patent U.S. Pat. No.3,918,200.

Patent FR 2,367 M describes the use of diosgenin as a medicinal productexhibiting antiphlogistic and anti-inflammatory activity which is usefulfor the treatment of rheumatic and vascular conditions. PatentFR-A-2,786,097 describes cosmetic slimming compositions comprisingapproximately 5% of extracts of Dioscorea opposita, having the effect ofacting on the lipid metabolism of adipocytes by limiting fataccumulation in the cell. Patent U.S. Pat. No. 5,804,211 describes aplant-based composition in the form of a nasal lotion, intended to limitor eliminate snoring, and containing an extract of Dioscorea, ginger,chamomile and a potassium or sodium salt. The extract of Dioscorea ispreferably Dioscorea villosa, used in a proportion of 0.01 to 0.4% byweight relative to the total weight of the composition.

The use of diosgenin in therapeutic compositions has also beendescribed, for example, in patent EP-A-873,125 relating to a compositioncombining diosgenin with vitamins, such as vitamin K and vitamin D,which can be administered orally or transdermally, for treatingosteoporosis.

It is also known that diosgenin, a steroidal saponin, is a precursor ofvarious steroids, and in particular of DHEA, which is an importanthormone in the human or animal body, produced by the adrenal glands, andwhich is converted to estrogen and testosterone. However, diosgenin isnot converted directly to progesterone, but to a hormone regulator.Nothing in the scientific literature makes it possible to suppose thatdiosgenin, in particular when it is administered topically, could havethe same activity as DHEA, in particular because the enzymes capable ofconverting it in the body have never been demonstrated. On the otherhand, it is possible to prepare DHEA from diosgenin in the laboratory.

Clinical studies carried out by the applicant have made it possible toshow that diosgenin derivatives, in particular diosgenin esters, haveproperties which are useful in dermatology and in cosmetics, and inparticular an action on the superficial musculoaponeurotic system whenthey are given by external or transdermal topical administration.

The subject of the present invention is therefore a composition whichcan be used topically in therapeutics and in cosmetology, comprising adiosgenin ester.

A subject of the invention is also a cosmetic and/or dermatologicalcomposition with a given content of diosgenin ester.

Finally, a subject of the invention is the use of a diosgenin ester forproducing a dermatological medicinal product which acts, by means of anaction similar to that of progesterone and of estrogens, on thesuperficial musculoaponeurotic system or on cellular estrogen andprogesterone receptors, for the treatment of skin conditions, and also acosmetic treatment process for the skin.

A subject of the present invention is also a composition having anintracellular or extracellular adaptogenic effect on the receptors ofcells of the epidermis, of the dermis of the superficialmusculoaponeurotic system, and of the hypodermis, and allowingapplication thereof in dermatology and in cosmetics, in particular forregenerating and restructuring the skin and, in general, for combatingthe signs of skin aging.

The cosmetic and/or dermatological composition of the invention isdistinguished in that it contains a diosgenin ester comprising a linearor branched alkylated ester chain of 1 to 30 carbon atoms.

The ester residue carried by the diosgenin can come from an acidpreferably containing 1 to 30 carbon atoms, and for example a fattyacid, an amino acid or alternatively an alpha-hydroxy acid. The fattyacid may be, for example, stearic acid, oleic acid or linoleic acid; theamino acid is preferably chosen from leucine, proline, thymidine,glucosamine and serine; the alpha-hydroxy acid is preferably chosen fromglycolic acid, lactic acid, mandelic acid and citric acid. It may bemost particularly advantageous to use diosgenin lactate or glycolate.

According to a variant in accordance with the present invention, analpha-hydroxy acid such as glycolic acid, lactic acid, thiolactic acidor thioglycolic acid, or one of their salts, is used together with thediosgenin ester.

In accordance with the present invention, it is particularlyadvantageous to use the diosgenin ester in combination with amucopolysaccharide, in particular a hydrolyzed mucopolysaccharide.

The studies carried out have shown that the diosgenin esters accordingto the invention, applied topically, for example in the form of a gel,cream or lotion, penetrate more effectively into the epidermis andexhibit an improved bioavailability compared with pure diosgenin.

The diosgenin ester can be prepared according to the usual techniques byreacting diosgenin with the corresponding acid, under suitable operatingconditions. The diosgenin can itself be obtained from an extract ofplants of the family Dioscoreaceae.

The extract of Dioscorea used in the present invention for preparing adiosgenin ester can be any extract of Dioscorea of the familyDioscoreaceae and, for example, Dioscorea opposita, Dioscorea composita,Dioscorea floriburida, Dioscorea villosa, Dioscorea hypoglauca, yam orwild yam, and preferably Dioscorea opposita. It is obtained in the formof an extract of the entire plant or, preferably, of the rhizome, as adry extract or essential oil. As indicated above, the diosgenin estercan be prepared by any suitable process, by means of the action of asuitable acid on the diosgenin or on the extract of Dioscorea having asatisfactory diosgenin content.

As indicated above, the compositions according to the present inventioncontain a given content of diosgenin ester, which can be relatively highcompared to the usual doses of dermatological active principles, and canbe between 0.05% and 80% by weight relative to the total weight of thecomposition, and preferably between 0.5% and 30% by weight. These estercontents can be chosen as a function of the method of administrationenvisioned. For example, in the case of a patch for transdermaladministration, the content of diosgenin ester can be advantageouslybetween 15 and 30% by weight.

The adaptogenic effect of the composition of the invention results fromthe high content of diosgenin ester providing an effective action whichresults in an activation of the effect similar to that of theprogesterone in the body, and a modulation of the cellular estrogen andprogesterone receptors.

In particular, the composition of the invention exerts its effects onthe superficial musculoaponeurotic system and on all the tissues ingeneral, by causing an increase in the sensitivity of the membrane orcytoplasmic receptors of the cells to circulating hormones. This effecttherefore makes it possible to compensate for the decrease in the numberof receptors by an increase in their sensitivity. The superficialmusculoaponeurotic system is a connective fibrous network containingfibroblasts sensitive to circulating estrogens and muscle fiberssensitive to progesterone.

This action is particularly effective on skin exhibiting signs of skinaging, by compensating for the hormonal loss by means of an increase inactivity associated with the increase in receptor sensitivity.

This activity can be advantageously exploited in treating the signs ofskin aging, by causing an increase in the thickness of the skin by meansof densification of the structure of the epidermis, of the dermis and ofthe hypodermis, and also of the dermis of the superficialmusculoaponeurotic system. The signs of skin aging are more particularlythose which are characterized by a relaxation of the structure of theskin and a decrease in the thickness of the skin and, as indicatedabove, the composition according to the invention acts by compensatingfor the hormonal loss by increasing the sensitivity of the estrogen andprogesterone receptors. This activity can also be taken advantage of indermatological and cosmetic surgery treatments, by providingdensification and a restructuring of the skin and an increase in muscletension, in particular in the face.

The composition of the invention can also be used advantageously fortreating various skin conditions and, for example, for treating burnsand cicatrization, and for an anti-edematous action in a combinedtreatment for, for example, venous insufficiency or localized adiposis.

The use of thiolactic acid or of thioglycolic acid, or one of theirsalts, in combination with the diosgenin ester according to theinvention proves to be particularly effective when used forstraightening keratin fibers, eyelashes or the hair.

Finally, the composition according to the invention is useful in thetreatment of excess weight. In fact, estrogens and progesterones are theknown hormonal agents of obesity of the limbs of the human body. In theadipocytes, the distribution of α-adrenergic receptors and ofβ-adrenergic receptors is approximately 85/15. Furthermore, it is knownthat the antero-internal face of the thigh comprises type I fats havingparticular sensitivity to estrogens and a high lipoprotein lipaseactivity, while the external face of the thigh has a particularsensitivity to progesterone, the anti-edematous action of which isknown. Thus, problems of hormonal regulation can cause a decrease, oreven a disappearance, of the β-adrenergic receptors which promotelipolysis more particularly in the pelvic region and on the inside ofthe knees, which can result in deformities in these regions. Inaddition, vascular disorders can further promote the disappearance ofthe β-receptors. As a result of this, there is an accumulation of fat onthe internal face of the thighs, in particular in a hyperestrogenicwoman exhibiting circulatory problems.

The composition according to the invention makes it possible to combatthis weight excess by reestablishing cutaneous trophism and a normalmicrocirculation allowing the release of certain β-adrenergic receptors.The reestablishment of lipolysis and of the perinodal microcirculationis demonstrated by an increase in the amplitude and a modification ofthe plethysmographic plots.

The diosgenin esters according to the present invention can beformulated according to the usual techniques and can be administered inthe form of emulsions, gels, masks, lotions, solutions for spraying,etc. The emulsions can be of the oil-in-water (O/W) or water-in-oil(W/O) type, for example gels or creams. Use may also be made ofencapsulation techniques and, for example, of the technique ofencapsulation in liposomes.

The emulsifier used for the composition of the invention is chosen as afunction of the formulations and of the conditions for administration.For example, the emulsifier can be chosen from high molecular weightcarboxyvinyl polymers (for example Carbopol®), polysorbates (for exampleTween 200 or Tween 600), sorbitan esters and, in particular, a sorbitanmonostearate, tristearate, monopalmitate and laurate (for example theemulsifiers known under the trademark Arlacel®). Use may also be made ofother emulsifiers, such as various derivatives of stearic acid orpalmitic acid, and, for example, PEG 1000 stearate or PEG 20® stearateor a C₁₂-C₂₀ ester of PEG 8 or PEG 9, stearic or palmitic acidglycerides, glycerylstearate, a polyethylene glycol stearate, a stearethor a ceteareth (for example ceteareth 20), or else polyglyceryl-2sesquioleate, polyoxyethylene cetyl ether, or an emulsifiable silicone.

Besides the emulsifiers mentioned above, the compositions can containvarious usual adjuvants chosen from those used in techniques forpreparing cosmetic and dermatological compositions, and for examplepreserving agents, thickeners, hydrophilic or lipophilic gelling agents,antioxidants, moisturizers, surfactants, fragrances, dyes, pigments,fillers and various additives intended to improve the physicalproperties of the composition. It may also be advantageous toincorporate into the composition of the invention sun-screening orsun-filtering agents which are active in the UVA and/or UVB range,chosen as a function of the desired degree of protection.

The diosgenin esters according to the present invention can be used forproducing a dermatological medicinal product acting by means of anaction on the superficial musculoaponeurotic system at the level of thecellular receptors, for the treatment of various skin disorders, andalso in a cosmetic treatment process for the skin, consisting inapplying to the area to be treated an effective amount of a diosgeninester, alone or in combination with acceptable excipients and supports.

The following examples illustrate the invention in greater detailwithout limiting the scope thereof.

EXAMPLE 1

Using the usual techniques of dermatological formulations, anexfoliating gel having the following composition, indicated in part byweight, is prepared: diosgenin lactate 1.0 glycolic acid 70.0moisturizer 5.0 lysine pyrrolidonecarboxylate 4.0 ethanol 5.0 ammoniumhydroxide 5.0 preserving agent 3.0 fragrance 0.5 water qs 100.0

This exfoliating gel can be used by application to the skin once a week.The trials carried out demonstrated an evident antiwrinkle andrestructuring effect from the end of the second week of application toareas exhibiting the signs of skin aging consisting of wrinkles, athinning of the skin and a relaxing of the skin. A tensioning effect onthe structure of the skin is notably observed from the first week oftreatment by means of the action on the superficial musculoaponeuroticsystem.

EXAMPLE 2

A slimming and anti-edematous cream having the composition by weightindicated below is prepared. diosgenin glycolate 5.0 hydrolyzedmucopolysaccharides 2.0 ethanol 5.0 moisturizer 5.0 C₁₂₋₂₀ PEG-8 ester7.0 cetearyl/palmitoyl octanoate 7.0 silk amino acids 2.0 extract ofginko biloba 1.0 troxerutin 1.0 preserving agent 0.2 fragrance 0.1 waterqs 100.0

This cream was applied once or twice a day to the legs of 30- to50-year-old patients, on the thighs and the knees.

The anti-edematous action is visible from the second day of treatment.Tissue drainage is particularly noticeable after liposuction of thethighs and the knees, preventing retractile fibrosis. In addition, theaction on the superficial musculoaponeurotic system is notable by virtueof the very rapid tensioning of the tissue, which makes it possible toapply this treatment to localized adiposis. Prolonged action results ina decrease in the excess weight due to the adaptogenic effect whichreactivates the progesterone-sensitive receptors.

EXAMPLE 3

A composition according to the present invention, which promotes hairregrowth, having following composition by weight, is prepared. diosgeninglycolate 20.0 hydrolyzed mucopolysaccharides 0.5 C₁₂₋₂₀ PEG-8 ester 8.0cetearyl octanoate 2.0 propylene glycol dicaprylate dicaprate 3.0 aescin0.5 extract of ginko biloba 1.0 preserving agent 0.2 water qs 100.0

1. A composition which is useful in therapeutics and in cosmetology, fortopical application, which comprises a diosgenin ester comprising alinear or branched alkylated ester chain of 1 to 30 carbon atoms.
 2. Thecomposition as claimed in claim 1, wherein the diosgenin ester comprisesdiosgenin lactate or diosgenin glycolate.
 3. The composition as claimedin claim 1, wherein the content of diosgenin ester is between 0.05% and80% by weight relative to the total weight of the composition.
 4. Thecomposition as claimed in claim 1, which also comprises an alpha-hydroxyacid or a salt of an alpha-hydroxy acid.
 5. The composition as claimedin claim 4, wherein the alpha-hydroxy acid is selected from the groupconsisting of glycolic acid, lactic acid, mandelic acid, citric acid,thiolactic acid and thioglycolic acid.
 6. The composition as claimed inclaim 1, which also comprises a mucopolysaccharide.
 7. (Canceled)
 8. Acosmetic treatment process for the skin, consisting in applying to thearea to be treated an effective amount of diosgenin ester as claimed inclaim
 1. 9. The composition as claimed in claim 2, wherein the contentof diosgenin ester is between 0.05% and 80% by weight relative to thetotal weight of the composition.
 10. A method of treating skinconditions by applying the composition of claim 1 to thereby exert anaction on the superficial musculoaponeurotic system or on the cellularestrogen and progesterone receptors.